Early life stress impairs DG formation by down regulating Autotaxin

描述（由申请人提供）：Autotaxin （ATX）是一种分泌的溶血磷脂酶，对胚胎发育期间神经干细胞（NSC）的正常增殖、迁移和存活至关重要。ATX的缺失是胚胎致死性的，这解释了缺乏关于其在围产期（出生后1-21天）支持NSC增殖中的作用的信息。本研究表明，海马（HP）中ATX的表达在围产期达到峰值，当小鼠幼仔在此期间暴露于慢性或急性应激时，ATX的表达急剧下降。我们还提供了初步数据，表明ATX基因杂合的21日龄幼崽减少了齿状回（DG）中NSC的增殖和颗粒细胞层（GCL）体积的减少。基于这些初步数据，我们假设发育中的HP中的ATX表达对正常DG发育至关重要（目的1），暴露于早期生活应激（ELS）的幼犬恢复正常水平的ATX将阻断ELS对DG发育的抑制作用（目的2），并且发育中的HP中的ATX表达受皮质酮水平的快速调节（目的3）。如果得到证实，这项工作将对之前的工作做出三个重要贡献。首先，它将首次证明正常

DESCRIPTION (provided by applicant): Autotaxin (ATX) is a secreted lysophospholipase that is essential for normal proliferation, migration, and survival of neural stem cells (NSC) during embryonic development. Deletion of ATX is embryonic lethal explaining the lack of information regarding its role in supporting NSC proliferation during the perinatal period (postnatal days 1-21). Here we show that expression of ATX in the hippocampus (HP) peaks during the perinatal period and is dramatically decreased when mice pups are exposed to chronic or acute stress during this period. We also present preliminary data that 21-day old pups that are heterozygous for the ATX gene have reduced NSC proliferation in the dentate gyrus (DG) and a decrease in granule cell layer (GCL) volume. Based on these preliminary data we hypothesize that ATX expression in the developing HP is essential for normal DG development (aim 1), that restoring normal levels of ATX to pups exposed to early life stress (ELS) will block the inhibitory effect that ELS has on DG development (aim 2), and that ATX expression in the developing HP is rapidly regulated by corticosterone levels (aim 3). If confirmed, this work will make three important contributions to previous work. First, it will demonstrate for the first time that normal DG formation, during the perinatal period, requires high expression levels of ATX. Second, it will show that corticosterone levels in the plasma tightly regulate ATX levels in the developing HP. Third, it will provide a novel molecular mechanism to explain how exposure to stress, during the perinatal period, affects DG development. We predict that ATX plays a similar role in DG development in humans, and that this work will identify a critical pathway by which abuse and neglect early in life cause long-term dysfunction in the HP of adult humans. .